Virtually all cells have the capacity to shift their relative reliance on glycolysis versus oxidative phosphorylation (OXPHOS), based on nutrient availability, environmental conditions, or stages of growth and differentiation. Additionally, some have suggested that shifts in energy metabolism can contribute to disease pathogenesis. For example, it has long been recognized that cancer cells exhibit higher rates of glycolysis (Warburg, Science 123:309 (1956)), perhaps to promote survival under hypoxic conditions or to support rapid cell proliferation. Recent studies have demonstrated that redirecting metabolism towards OXPHOS, using dichloroacetate, can actually retard tumor growth (Bonnet et al., Cancer Cell 11:37 (2007)).
Conversely, recent studies in cellular and animal models have shown that partial inhibition of OXPHOS via genetic or pharmacologic means can suppress the toxicity of disease alleles associated with neurodegenerative disorders (Buttner et al., J Biol Chem 283:7554 (2008); Fukui et al, Proc Natl Acad Sci USA 104:14163 (2007); and Varma et al., Proc Natl Acad Sci USA 104:14525 (2007)) as well as in suppressing the cell death observed in animal models of stroke (Huber et al., J Neurosci Res 75:441 (2004)) and cardiac ischemia reperfusion (Chen et al., Am J Physiol Cell Physiol 292:C137 (2007)). The underlying mechanism of protection is unclear but it has been suggested that flux through a damaged or compromised mitochondrial respiratory chain may contribute to the pathology, and that by redirecting energy metabolism towards glycolysis, it may be possible to minimize oxidative damage and suppress apoptosis (Jeong et al., Biochem Biophys Res Commun 313:984 (2004); and Hunter et al., Int J Radiat Biol 83:105 (2007)).
Clinically useful agents with which to shift a cell's reliance from OXPHOS to glycolysis are currently unavailable. For example, classic poisons of OXPHOS, such as rotenone, antimycin, cyanide, and oligomycin, have many disadvantages by: i) acting quickly and directly to interrupt respiration with extremely high potency and efficacy; ii) acutely depleting ATP in oxidative tissues, thereby stalling the numerous biochemical pathways coupled to the respiratory chain; iii) causing rapid cell toxicity; and iv) causing death in humans, at even at low doses.